Heteroaromatic N-oxides Research Articles

Complexes of Zinc-Coordinated Heteroaromatic N-Oxides with Pyrene: Lewis Acid Effects on the Multicenter Donor-Acceptor Bonding.

4-Nitroquinoline-N-oxide (NQO) and 4-nitropyridine-N-oxide (NPO) are important precursors for the synthesis of substituted heterocycles while NQO is a popular model mutagen and carcinogen broadly used in cancer research; intermolecular interactions are critical for their reactions or functioning in vivo. Herein, the effects of the coordination of N-oxide's oxygen atom to Lewis acids on multicenter donor-acceptor bonding were explored via a combination of experimental and computational studies of the complexes of NQO and NPO with a typical π-electron donor, pyrene. Coordination with ZnCl2 increased the positive electrostatic potentials on the surfaces of these π-acceptors and lowered the energy of their LUMO. Analogous effects were observed upon the protonation of the N-oxides' oxygen or bonding with boron trifluoride. The interaction of ZnCl2, NPO, or NQO and pyrene resulted in the formation of dark co-crystals comprising π-stacked Zn-coordinated N-oxides and pyrene similar to that found with protonated or (reported earlier) BF3-bonded N-oxides. Computational studies indicated that the coordination of N-oxides to zinc(II), BF3, or protonation led to the strengthening of the multicenter bonding of the nitro-heterocycle with pyrene, and this effect was related both to the increased electrostatic attraction and molecular-orbital interactions in their complexes.

Redox Proteomic Profile of Tirapazamine-Resistant Murine Hepatoma Cells.

3-Amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ) and other heteroaromatic N-oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities. Their action is attributed to the enzymatic single-electron reduction to free radicals that initiate the prooxidant processes. In order to clarify the mechanisms of aerobic mammalian cytotoxicity of ArN→O, we derived a TPZ-resistant subline of murine hepatoma MH22a cells (resistance index, 5.64). The quantitative proteomic of wild-type and TPZ-resistant cells revealed 5818 proteins, of which 237 were up- and 184 down-regulated. The expression of the antioxidant enzymes aldehyde- and alcohol dehydrogenases, carbonyl reductases, catalase, and glutathione reductase was increased 1.6-5.2 times, whereas the changes in the expression of glutathione peroxidase, superoxide dismutase, thioredoxin reductase, and peroxiredoxins were less pronounced. The expression of xenobiotics conjugating glutathione-S-transferases was increased by 1.6-2.6 times. On the other hand, the expression of NADPH:cytochrome P450 reductase was responsible for the single-electron reduction in TPZ and for the 2.1-fold decrease. These data support the fact that the main mechanism of action of TPZ under aerobic conditions is oxidative stress. The unchanged expression of intranuclear antioxidant proteins peroxiredoxin, glutaredoxin, and glutathione peroxidase, and a modest increase in the expression of DNA damage repair proteins, tend to support non-site-specific but not intranuclear oxidative stress as a main factor of TPZ aerobic cytotoxicity.

Heteroaromatic N-Oxides Modified with a Chiral Oxazoline Moiety, Synthesis and Catalytic Applications

Interesting properties of N-oxides and pyridine oxazoline compounds have become the starting point to synthesize compounds connecting both groups. A multi-step synthesis of a series of chiral oxazoline substituted pyridine N-oxides, alkyl derived of pyridine N-oxides, bipyridine N-oxides, and isoquinoline N-oxides, based on amino alcohols derived from natural amino acids or other previously prepared, is presented herein. Various synthetic pathways have been designed and tested according to the properties and limitations imposed by the target products. The encountered problems related to the stability of the products were discussed. The resulting compounds (eighteen structures) were tested as catalysts in th e allylation of benzaldehyde (obtaining up to 79% ee) as well as in nitroaldol reaction (obtaining up to 48% ee).

Copper-catalyzed redox neutral ketoalkylation of Csp2–H bonds via C–C bond cleavage

An efficient copper-catalyzed ketoalkylation of Csp2–H bonds with cycloalkyl silyl peroxides under mild conditions is presented. A series of Csp2–H bonds in quinoxalin-2(1H)-ones, heteroaromatic N-oxides and quinones were amenable to this protocol.

Aerobic Cytotoxicity of Aromatic N-Oxides: The Role of NAD(P)H:Quinone Oxidoreductase (NQO1).

Derivatives of tirapazamine and other heteroaromatic N-oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities, which are typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the role of NAD(P)H:quinone oxidoreductase (NQO1) in ArN→O aerobic cytotoxicity. We synthesized 9 representatives of ArN→O with uncharacterized redox properties and examined their single-electron reduction by rat NADPH:cytochrome P-450 reductase (P-450R) and Plasmodium falciparum ferredoxin:NADP+ oxidoreductase (PfFNR), and by rat NQO1. NQO1 catalyzed both redox cycling and the formation of stable reduction products of ArN→O. The reactivity of ArN→O in NQO1-catalyzed reactions did not correlate with the geometric average of their activity towards P-450R- and PfFNR, which was taken for the parameter of their redox cycling efficacy. The cytotoxicity of compounds in murine hepatoma MH22a cells was decreased by antioxidants and the inhibitor of NQO1, dicoumarol. The multiparameter regression analysis of the data of this and a previous study (DOI: 10.3390/ijms20184602) shows that the cytotoxicity of ArN→O (n = 18) in MH22a and human colon carcinoma HCT-116 cells increases with the geometric average of their reactivity towards P-450R and PfFNR, and with their reactivity towards NQO1. These data demonstrate that NQO1 is a potentially important target of action of heteroaromatic N-oxides.

Chemical and Biochemical Reactions of Aromatic Furazan Compounds

Aromatic furazan has numerous pharmacologic and industrial applications. As part of our work on aromatic furazan chemistry and biochemistry, benzofurazan N-oxides, on irradiation using a high-pressure mercury lamp with a Pyrex filter in acetonitrile containing a little water, afforded 1H-azepine-2,7-dione. Mechanistic studies on the photoreaction using a low-pressure mercury lamp and photosensitizer suggest that photosensitized formation of 1H-azepine-2,7-dione with the aromatic hydrocarbon may be carried out by reabsorption of fluorescence. Quinoxaline 1,4-dioxide, phenazine 5,10-dioxide, and pyrido[2,3-b]pyrazine derivatives were synthesized from the corresponding aromatic or heteroaromatic furazan N-oxides by silica gel or molecular sieves under solvent-free conditions using microwave irradiation. The toxicities of some benzofurazans were examined on Escherichia coli; these may due to their reduction within the E. coli cell and their reoxidization by molecular dioxygen to form superoxide and hydrogen peroxide. The formation of 4,7-dicyanobenzofurazan anion radical in the E. coli cell suspension-4,7-dicyanobenzofurazan-glucose system in the absence of O2 was followed by ESR spectroscopy. 4,7-Dimethylbenzofurazan was transformed by 1O2 produced by irradiation of C60 into 4,7-dimethylbenzofurazan 4,7-endoperoxide. The endoperoxide decomposed back to 4,7-dimethylbenzofurazan at room temperature. 4,7-Dimethylbenzofurazan was transformed by irradiation with the third harmonic of a Quanta-Ray Nd:YAG laser (355 nm) into (2Z,4Z)-2,5-dimethylhexa-2,4-dienedinitrile monoxide. Irradiation of 4,7-dimethylbenzofurazan yielded a photoproduct with a quantum yield 0.48 and chemical yield 99%.

Heteroaromatic N-Oxides in Asymmetric Catalysis: A Review.

An increasing interest in the synthesis and use of optically active pyridine N-oxides as chiral controllers for asymmetric reactions has been observed in the last few years. Chiral heteroaromatic N-oxides can work as powerful electron-pair donors, providing suitable electronic environments in the transition state formed within the reaction. The nucleophilicity of the oxygen atom in N-oxides, coupled with a high affinity of silicon to oxygen, represent ideal properties for the development of synthetic methodology based on nucleophilic activation of organosilicon reagents. The application of chiral N-oxides as efficient organocatalysts in allylation, propargylation, allenylation, and ring-opening of meso-epoxides, as well as chiral ligands for metal complexes catalyzing Michael addition or nitroaldol reaction, can also be found in the literature. This review deals with stereoselective applications of N-oxides, and how the differentiating properties are correlated with their structure. It contains more recent results, covering approximately the last ten years. All the reported examples have been divided into five classes, according to the chirality elements present in their basic molecular frameworks.

Kinetics of Flavoenzyme-Catalyzed Reduction of Tirapazamine Derivatives: Implications for Their Prooxidant Cytotoxicity.

Derivatives of tirapazamine and other heteroaromatic N-oxides (ArN→O) exhibit promising antibacterial, antiprotozoal, and tumoricidal activities. Their action is typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the mechanism(s) of aerobic mammalian cell cytotoxicity of ArN→O performing the parallel studies of their reactions with NADPH:cytochrome P-450 reductase (P-450R), adrenodoxin reductase/adrenodoxin (ADR/ADX), and NAD(P)H:quinone oxidoreductase (NQO1); we found that in P-450R and ADR/ADX-catalyzed single-electron reduction, the reactivity of ArN→O (n = 9) increased with their single-electron reduction midpoint potential (E17), and correlated with the reactivity of quinones. NQO1 reduced ArN→O at low rates with concomitant superoxide production. The cytotoxicity of ArN→O in murine hepatoma MH22a and human colon adenocarcinoma HCT-116 cells increased with their E17, being systematically higher than that of quinones. The cytotoxicity of both groups of compounds was prooxidant. Inhibitor of NQO1, dicoumarol, and inhibitors of cytochromes P-450 α-naphthoflavone, isoniazid and miconazole statistically significantly (p < 0.02) decreased the toxicity of ArN→O, and potentiated the cytotoxicity of quinones. One may conclude that in spite of similar enzymatic redox cycling rates, the cytotoxicity of ArN→O is higher than that of quinones. This is partly attributed to ArN→O activation by NQO1 and cytochromes P-450. A possible additional factor in the aerobic cytotoxicity of ArN→O is their reductive activation in oxygen-poor cell compartments, leading to the formation of DNA-damaging species similar to those forming under hypoxia.

TsCl-promoted sulfonylation of quinoline N-oxides with sodium sulfinates in water

An eco-friendly protocol for the synthesis of various 2-sulfonyl quinolines/pyridines through sulfonylation of heteroaromatic N-oxides with sodium sulfinates in water at ambient temperature under metal- and oxidant-free conditions has been developed. The mild reaction conditions, high reaction efficiency, operational simplicity, short reaction time and remarkable functional-group compatibility make the developed protocol very attractive for the preparation of 2-sulfonyl N-heteroaromatic compounds.

Complexes of Diiodine with Heteroaromatic N-Oxides: Effects of Halogen-Bond Acceptors in Halogen Bonding.

Halogen bonding (XB) in complexes of diiodine with heteroaromatic N-oxides was examined via a combination of UV-vis spectral and X-ray structural measurements, as well as computational analysis. While all of these associates were formed by analogous I···O bonds, they showed considerable variations of formation constants (5-1500 M-1) and intermolecular I···O bond length (2.3-3.2 Å). In the solid state, both atoms of I2 molecules were involved in XB, and the I···O separations were determined by the electron-donor abilities of N-oxides and the strength of the bonding on the opposite side of the ditopic XB donor. The solution-phase formation constants of 1:1 complexes, K, as well as magnitudes of the calculated interaction energies, ΔE, increased with the shift of the values of the most negative potentials on the surfaces of N-oxides' oxygen atoms, Vmin, toward more negative values. Yet, the interatomic contacts consistently deviated from the locations of Vmin. Instead, the structures of complexes were well suited for highest occupied molecular orbital/lowest unoccupied molecular orbital interactions of reactants. The values of K, ΔE, and the intermolecular distances dI···O in the calculated complexes were highly correlated with the charge-transfer interaction energies derived from the natural bond orbital analysis. This indicated that, besides electrostatic, molecular orbital interactions play a substantial role in XB between diiodine and N-oxides. This conclusion was supported by the analysis of the complexes using the quantum theory of atoms in molecules, noncovalent interaction index, and density overlap region indicator, which showed that the covalent character of I···O bonding increases with the rise of interaction energies in the complexes.

Catalytic Selective Metal-Free Cross-Coupling of Heteroaromatic N-Oxides with Organosilanes.

A metal-free, regioselective C-H functionalization of heteroaromatic N-oxides has been developed. The method enables the synthesis of various benzylated and alkynylated N-heterocycles in a transition-metal-free manner employing organosilanes as coupling partners. The unanticipated reactivity has been exploited for the synthesis of a number of symmetrical disubstituted acetylenes from ethynyltrimethylsilane via carbon-silicon bond metathesis.

Effects of Supramolecular Architecture on Halogen Bonding between Diiodine and Heteroaromatic N-Oxides

Cocrystallization of diiodine with a series of heteroaromatic N-oxides produced three types of halogen-bonded associates: (a) alternating chains comprising I2 molecules bridged by oxygen atoms of N-oxides of pyridine, quinoline, or 4-methylpyridine; (b) discrete 2:1 complexes, in which diiodine links a pair of acridine N-oxide molecules; and (c) amphoteric 1:1 adducts, in which one end of each diiodine molecule is halogen-bonded to N-oxide of 4-methoxypyridine or 4-chloroquinoline, and another diiodine’s end forms contacts with the other I2 molecules. In all cases, halogen bonds between diiodine and N-oxides are characterized by nearly linear I–I···O angles, close to perpendicular dihedral C–N–O···I angles and N–O···I angles of about 110°. The halogen bond length in the 1:1 adducts is about 0.3 A shorter than those in the 2:1 associates and in the infinite chains. Computational analyses confirmed that the variations in I···O separations are related predominantly to the distinct effects of halogen bond com...

Direct C-H Cyanoalkylation of Heteroaromatic N-Oxides and Quinones via C-C Bond Cleavage of Cyclobutanone Oximes.

A direct C-H cyanoalkylation of heteroaromatic N-oxides and quinones with cyclobutanone oximes is reported. This redox-neutral, operationally simple cyanoalkylation reaction is successfully amenable to a wide range of heteroaromatic N-oxides, quinones, and cyclobutanone oximes. A novel catalytic system consisting of a nickel source proved crucial for cleavage of the C-C bond of cyclobutanone oximes and for selective C-C bond formation over β-hydride elimination. Mechanistic studies suggest that a radical intermediate might be involved in this transformation.

Effects of N-Oxidation on Heteroaromatic Macrocycles: Synthesis, Electronic Structures, Spectral Properties, and Reactivities of Tetraazaporphyrin meso-N-Oxides.

Heteroaromatic N-oxides such as pyridine and quinoline N-oxides are well studied in organic chemistry, and N-oxide formation has long been utilized for tuning the reactivities of heteroaromatics. However, the scope of aromatic N-oxidation is still restricted to relatively small azine or azole skeletons, and there has been little investigation of the photophysical/chemical effects of N-oxidation on larger heteroaromatic systems. Here, the synthesis and unique properties of new macrocyclic heteroaromatic N-oxides, tetraazaporphyrin (TAP) meso-N-oxides, are reported. N-Oxidation of TAP reduced the 18π-aromaticity of the TAP ring compared with that of the parent TAP owing to the cross-conjugated resonance structure. The optical properties of TAPs were significantly changed by N-oxidation: the N-oxides did not exhibit azaporphyrin-like but instead porphyrin-like optical properties, that is, weak Q absorption bands, strong Soret absorption bands, and weak fluorescence. These features can be explained by the near-degenerate frontier molecular orbitals resulting from N-oxide formation. Singlet oxygen quantum yields were greatly increased to almost quantitative levels by N-oxidation. The N-oxides showed near-IR-responsive photoredox properties and were suitable as both oxidants and sensitizers for oxidation reactions. Protonation of the N-oxides restored TAP-like intense Q bands and red fluorescence, offering a potential design strategy for fluorescence switches.

In Situ Generated HypoIodite Activator for the C2 Sulfonylation of Heteroaromatic N-oxides.

A mild approach for direct C2 sulfonylation of heteroaromatic N-oxides with sulfonyl hydrazides affording 2-sulfonyl quinolines/pyridines has been developed. A variety of heteroaromatic N-oxides and sulfonyl hydrazides participate effectively in this transformation which uses hypoiodites (generated in situ from NaI and TBHP) as a means of substrate activators. In this reaction, the N-oxide plays a dual role, acting as a traceless directing group as well as a source of oxygen atom.

Copper-Catalyzed Direct Sulfoximination of Heteroaromatic N-Oxides by Dual C-H/N-H Dehydrogenative Cross-Coupling.

A dual C-H/N-H dehydrogenative coupling of quinoline-type N-oxides with sulfoximines that leads to N-(hetero)arylsulfoximines in high yields has been realized by using a catalytic amount of CuBr in air. The method does not require any additional ligand, base, reactivity modifier or oxidant and provides a practical route towards a series of sulfoximidoyl-functionalized quinolines and derivatives.

ChemInform Abstract: Recent Developments in the Chemistry of Heteroaromatic N‐Oxides

AbstractReview: [72 refs.

Crystal structure of molecular complexes of zinc(II) tetraphenylporphyrin with pyridine and quinoline N-oxides

The structure of molecular complexes of zinc(II) tetraphenylporphyrin (Zn-TPP) with 4-methoxy- and trans-2-(4-dimethylaminostyryl)pyridine and 4-methoxy-, 4-nitro, and 4-chloroquinoline N-oxides was studied by X-ray diffraction analysis. Heteroaromatic N-oxides, like aniline derivatives, are coordinated at an angle of 26°–32° to the porphyrin ring plane, whereas pyridine ligands are coordinated almost perpendicularly to this plane. It is suggested that just such coordination peculiarities are responsible for the difference in the thermodynamic parameters of Zn-TPP with pyridine-based ligands (linear relationship between ΔH0 and ΔS0, high heat effect of the process), and N-oxides, aniline derivatives (low ΔH0 values, quasi-isenthalpic processes).

ChemInform Abstract: Dimerization of Heteroaromatic N‐Oxides under Metal‐Free Conditions.

A novel procedure for the dimerization of heteroaromatic N-oxides under transition-metal-free conditions has been developed. The protocol is effective and convenient. The biheteroaromatic mono N-oxides products were obtained in up to 93% yield.

Recent Developments in the Chemistry of Heteroaromatic N-Oxides

Selected developments in the chemistry of heteroaromatic <i>N</i>-oxides since 2001 are presented in this review. The use of these <i>N</i>-oxides, both in late-transition-metal-catalyzed oxidations of carbon–carbon triple bonds and in regioselective C–H functionalizations of the heteroarene, are contemporary topics of interest and the focus of the discussion. 1 Introduction 2 Synthesis of Heteroaromatic <i>N</i>-Oxides 2.1 Direct Oxidation of Hindered Heteroarenes 2.2 Through Construction of Heteroaromatic Rings 3 Heteroaromatic <i>N</i>-Oxides as Oxidants 3.1 Alkyne Oxidation 3.2 Allene Oxidation 3.3 Carbene Oxidation 4 Heteroaromatic <i>N</i>-Oxides as Substrates 4.1 Deoxygenative <i>ortho</i>-C–H Functionalization with Prior Activation 4.2 Deoxygenative <i>ortho</i>-C–H Functionalization with Nonstabilized Carbanions 4.3 Nondeoxygenative C–H Functionalization 4.3.1 <i>ortho</i>-C–H Functionalization 4.3.2 <i>N</i>-Oxide Directed <i>ortho</i>-Alkyl C–H Functionalization 4.3.3 <i>N</i>-Oxide Directed Remote C–H Functionalization 4.4 1,3-Dipolar Cycloaddition 5 Conclusion and Outlook